Diminished LDL receptor and high heparin binding of apolipoprotein E2 sendai associated with lipoprotein glomerulopathy

Abstract

Variants of apolipoprotein E (apoE) have been linked to lipoprotein glomerulopathy, a new glomerular disease characterized by the deposition of lipoproteins in mesangial capillaries. One third of affected patients are heterozygous for apoE2 Sendai (Arg145→Pro). Variants of apoE can also produce type III hyperlipoproteinemia (HLP). Recessive type III HLP is caused by apoE2 (Arg158→Cys), a mutant with diminished low-density lipoprotein (LDL) receptor binding but half-normal heparin binding. Dominant type III HLP is caused by mutations that markedly alter heparin binding but modestly reduce receptor binding. This study examined whether apoE2 Sendai (Arg145→Pro) was functionally different from type III HLP-producing apoE variants by expressing apoE3, apoE2 (Arg158→Cys), apoEI (Arg146→Glu), a dominant apoE variant, and apoE2 Sendai (Arg145→Pro) in the baculovirus system. LDL receptor binding was studied using recombinant apoE complexed to phospholipid vesicles and to very low-density lipoprotein from a patient with familiar apoE deficiency. Compared with apoE3, receptor-binding activities of apoE2 (Arg158→Cys), apoEl (Arg146→Glu), and apoE2 Sendai (Arg145→Pro) all were less than 5%. Heparin-binding activities were 53%, 23%, and 66%, respectively, of apoE3. The distribution of apoE2 Sendai among the major plasma lipoprotein fractions was similar to that of apoE3 and apoE2 (Arg158→Cys). ApoE2 Sendai (Arg145→Pro) represents the only known mutation within the heparin-binding domain of apoE (residues 142 through 147), revealing diminished receptor binding and almost normal heparin binding. These unique characteristics of apoE2 Sendai (Arg145→Pro) may relate to the development of lipoprotein glomerulopathy.